Recent evidence has shown that many of the cell surface receptors that initiate pathways leading to NF-kB activation show a dualistic behavior, with outputs that lead either to inflammatory responses or death. The nearly ubiquitous expression of receptors in the TNF receptor superfamily and the increasing evidence that many cell types outside the immune system are affected by TNF and related cytokines in ways that are substantially broader than previously supposed argue for a closer examination of the cell specific features of NF-kB activation. In this application we propose to undertake a search for new cDNAs that have the power to induce NF-kB activity when overexpressed in a reporter cell line, and to explore the physiological partners for those proteins by two-hybrid, pulldown and epistasis experiments in culture. In addition, we propose to gain insight into the natural physiology of NF-kB activation by studying the contexts that lead to reporter gene activation in vivo.